The Ah receptor belongs to a specific class of transcription factors, the basic helix-loop-helix/Per-Arnt-Sim domain (bHLH/PAS) proteins, which is emerging as a battery of regulatory factors seemingly designed to respond to environmental cues (Gu et al., 2000). The ligand-activated Ah receptor mediates transcriptional activation of a network of genes encoding drug metabolizing enzymes, e.g. CYP1A1, which function in the oxidative metabolism of xenobiotics (Pohjanvirta and Tuomisto, 1994). There exists a paucity of data on other target genes of the Ah receptor. In addition to genes encoding drug metabolizing enzymes, it has been reported that the Ah receptor directly or indirectly regulates the expression of the cell cycle regulator p27/kip1 in certain cells (Kolluri et al., 1999).
Transgenic mice expressing a constitutively active dioxin/aryl hydrocarbon receptor (CA-AhR) develop tumours of the glandular stomach from 3-4 months of age that correlate with increased mortality beginning at 6-9 months of age depending on founder line and sex of the animals (Andersson et al., 2002). Male CA-AhR mice develop more severe tumours than age-matched females. The tumours originate from the mucosa, penetrate through the muscularis mucosa and expand into the submucosa, muscularis propria and the subserosa. The well-studied target gene of the Ah receptor, CYP1A1, is expressed in many tissues of the CA-AhR mice also including the tumours, demonstrating transcriptional activity of the CA-AhR. However, neither CYP1A1 nor p27/kip1 have previously been implicated in the development of stomach tumours in humans or in experimental animals.
The tumours also show intestinal metaplasia. Exposure of experimental animals to Ah receptor ligands such as PCBs induce stomach tumours in rhesus monkeys (Allen and Norback, 1973; Becker et al., 1979) as well as intestinal metaplasia and adenocarcinoma of the glandular stomach in rat (Morgan et al., 1981). None of the target genes that to date have been described to be directly regulated by the Ah receptor can explain the phenotype observed in the stomach of the CA-AhR mice.
There is a constant need for new drugs and methods of treatment for the combat of cancer, as well as for new approaches for identifying substances for use in such drugs and methods. One problem underlying the present invention is how to find substances and methods for the prevention, alleviation, or treatment of gastrointestinal tumours.